[Clinical use of botulinum toxin type A in pain medicine]. / Klinische Anwendung von Botulinumtoxin Typ A in der Schmerzmedizin.

Botulinum toxin has been used for decades in the treatment of a variety of painful diseases. Botulinum toxin not only blocks neuromuscular transmission, but also the secretion of neuropeptides, such as substance P, glutamate and calcitonin gene-related peptide (CGRP) and thus inhibits neurogenic inflammation. In addition, it has a modulatory pain-relieving effect via retrograde transport into the central nervous system. In addition to approval for the treatment of dystonia or spasticity, onabotulinum toxin A is also approved for the prophylaxis of chronic migraine if the oral prophylactic migraine medication has had an insufficient effect or has not been tolerated. In addition, botulinum toxin is also recommended in guidelines as a third-line treatment for neuropathic pain, but in Germany this is an off-label application. This article provides an overview of the current clinically relevant areas of application of botulinum toxin in the field of pain medicine.

Distraction by a cognitive task has a higher impact on electrophysiological measures compared with conditioned pain modulation.

BACKGROUND: Conditioned pain modulation (CPM) evaluates the effect of a painful conditioning stimulus (CS) on a painful test stimulus (TS). Using painful cutaneous electrical stimulation (PCES) as TS and painful cold water as CS, the pain relief was paralleled by a decrease in evoked potentials (PCES-EPs). We now aimed to compare the effect of CPM with cognitive distraction on PCES-induced pain and PCES-EP amplitudes. METHODS: PCES was performed using surface electrodes inducing a painful sensation of 60 (NRS 0-100) on one hand. In a crossover design healthy subjects (included: n = 38, analyzed: n = 23) immersed the contralateral hand into 10 °C cold water (CS) for CPM evaluation and performed the 1-back task for cognitive distraction. Before and during the CS and 1-back task, respectively, subjects rated the pain intensity of PCES and simultaneously cortical evoked potentials were recorded. RESULTS: Both CPM and cognitive distraction significantly reduced PCES-EP amplitudes (CPM: 27.6 ± 12.0 µV to 20.2 ± 9.5 µV, cognitive distraction: 30.3 ± 14.2 µV to 13.6 ± 5.2 µV, p < 0.001) and PCES-induced pain (on a 0-100 numerical rating scale: CPM: 58 ± 4 to 41.1 ± 12.3, cognitive distraction: 58.3 ± 4.4 to 38.0 ± 13.0, p < 0.001), though the changes in pain intensity and PCES-amplitude did not correlate. The changes of the PCES-EP amplitudes during cognitive distraction were more pronounced than during CPM (p = 0.001). CONCLUSIONS: CPM and cognitive distraction reduced the PCES-induced pain to a similar extent. The more pronounced decrease of PCES-EP amplitudes after distraction by a cognitive task implies that both conditions might not represent the general pain modulatory capacity of individuals, but may underlie different neuronal mechanisms with the final common pathway of perceived pain reduction.

[Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: A systematic review of randomized controlled studies]. / Wirksamkeit, Verträglichkeit und Sicherheit von Cannabinoiden bei neuropathischen Schmerzsyndromen : Eine systematische Übersichtsarbeit von randomisierten, kontrollierten Studien.

BACKGROUND: Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. MATERIAL AND METHODS: A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. RESULTS: We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2 with nabilone and 1 with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12). CONCLUSION: Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.

[The rubber hand illusion in patients with complex regional pain syndrome. Successful illusion induction shows multisensory integration]. / Die Gummihandillusion bei CRPS-Patienten. Erfolgreiche Illusionsinduktion zeigt intakte multisensorische Integration.

Next to neurogenic inflammation and pathological sympathetic-afferent coupling, functional imaging studies have shown the crucial role of maladaptive cortical reorgansation in the pathophysiology of CRPS. Bilateral neuroplastic alterations in the somatosensory cortex seem to play a substantial role in the dysfunctional sensory processing of stimuli. The aim was to investigate the multimodal integration of sensory and visual stimuli into the body scheme and the influence of higher cognitive body representation in the integration of multimodal schema, body relevant stimuli in patients with CRPS. The investigated sample included 24 patients suffering from CRPS of the upper extremities, 21 patients with chronic hand pain of other origins and 24 healthy probands. The rubber hand illusion was carried out for the first time in patients with complex regional pain syndrome (CRPS). The reprentations show that the patients can integrate a rubber hand in their body representation to the same degree as healthy patients. The intact experience of the rubber hand illusion by CRPS patients indicates that the integration of congruent visual and tactile stimuli in CRPS is intact.

Childhood diabetic neuropathy: functional impairment and non-invasive screening assessment.

AIM: Sensory diabetic neuropathy, determined by nerve conduction studies, is common in children with Type 1 diabetes. Diabetic neuropathy diagnoses are rarely made in paediatric daily care because they are asymptomatic, vibration detection is mostly normal and nerve-conduction testing is impractical. The present study aims to: (1) describe somatosensory dysfunction in children with diabetes, (2) test whether diabetes duration and HbA(1c) are related to somatosensory dysfunction and (3) identify the best screening test for large-fibre dysfunction, as indicated by nerve conduction studies. METHODS: Forty-five children (age 13.2 ± 2.5 years) with Type 1 diabetes for 6.7 ± 2.5 years and matched control subjects were assessed by neurological examinations, nerve conduction tests and quantitative sensory testing on the feet using the protocol of the German Research Network on Neuropathic Pain. Abnormal nerve conduction was used as gold standard to define neuropathies. RESULTS: We found a high prevalence of mechanical (38%) and thermal (24%) hypoesthesia often associated with hyperalgesia (47%). Tactile hypoesthesia (33%) was more frequent than pallhypaesthesia (11%). Only cold detection and mechanical pain thresholds were related to HbA(1c). Tactile hypoesthesia had the highest sensitivity (75%), specificity (89%) and positive (75%) and negative (89%) predictive values for neuropathies defined by nerve conduction tests (31% abnormal). CONCLUSIONS: Almost half of the children with diabetes have subclinical large- and small-fibre neuropathies. Tactile detection was better than vibration for neuropathy assessment. Quantitative sensory testing is a valuable tool for assessment of neuropathy as well as a target of interventional studies in children with diabetes.

[Comparable disorder of the body schema in patients with complex regional pain syndrome (CRPS) and phantom pain]. / Vergleichbare Störung des Körperschemas bei Patienten mit komplexem regionalem Schmerzsyndrom (CRPS) oder Phantomschmerz.

In patients with complex regional pain syndrome (CRPS) a disruption of the body schema has been shown in an altered cortical representation of the hand and in delayed reaction times (RT) in the hand laterality recognition task. However, the role of attentional processes or the effect of isolated limb laterality training has not yet been clarified. The performance of healthy subjects (n = 38), CRPS patients (n = 12) and phantom limb pain (PLP) patients (n = 12) in a test battery of attentional performance (TAP) and in a limb laterality recognition task was compared and the effect of limb laterality training in CRPS patients and healthy subjects evaluated. The RTs of both CRPS and PLP patients were significantly slower than those of healthy subjects despite normal TAP values. The CRPS and PLP patients showed bilaterally delayed RTs. Through training RTs improved significantly but the RTs of CRPS patients remained slower than those of healthy subjects. In this study an equal disruption of the body schema was found in both CRPS and PLP patients which cannot be accounted for by attentional processes. For CRPS patients this disorder cannot be fully reversed by isolated limb laterality recognition training.

Conditioned pain modulation using painful cutaneous electrical stimulation or simply habituation?

BACKGROUND AND AIMS: Cold pressor test was recently reported to significantly reduce painful cutaneous electrical stimulation (PCES)-induced pain and corresponding evoked potentials (PCES-EPs), but whether this reduction is an effect of conditioned pain modulation (CPM) remains unknown. To what extent these findings are confounded by habituation is also unknown. We thus compared the effect of CPM and habituation on PCES-induced pain and PCES-EPs and analysed whether increased attention by a random change of electric stimulation would intensify this possible habituation effect. METHODS: Three custom-built concentric surface electrodes were used to induce a pain intensity of 60 on a 0-100 numerical rating scale (NRS) among 29 healthy subjects (age 20-35y, 16 females). PCES-EPs (including P0N1 and N1P1 amplitudes, N1 latencies) were assessed over Cz. Group A received 14 min of electrical stimulation with constant intensity followed by 14 min of electrical stimulation with variable intensities, group B vice versa. Afterwards, subjects perceived cold-water pain (10 °C) contralaterally as conditioning stimulus to assess CPM. Statistical analysis was conducted with ANOVA and t-test. RESULTS: In both groups, N1 latencies remain unchanged, but the intensity of PCES-induced pain (12 ± 17%; p < 0.01) and N1P1 amplitudes of PCES-EPs (10 ± 16%; p < 0.05) decreased significantly during the 14-min PCES with constant current intensity. CPM also significantly reduced pain ratings (36 ± 19%; p < 0.001) and amplitudes (37.2 ± 15.8%), p < 0.001). A significant decline of P0N1 amplitudes occurred only during CPM (18 ± 61%; p < 0.001). CONCLUSION: We found a significant effect of habituation on PCES-induced pain and PCES-EPs, although the effect of CPM was significantly larger and could not be explained by habituation alone. SIGNIFICANCE: Painful cutaneous electrical stimulation leads to moderate habituation of pain and evoked potential amplitudes, but the conditioned pain modulation effect using this method is significantly larger, which might indicate a different mechanism in central processing.

Presence of hyperalgesia predicts analgesic efficacy of topically applied capsaicin 8% in patients with peripheral neuropathic pain.

BACKGROUND: Topical high-dose capsaicin acting on TRPV1 receptors and inducing an intraepidermal decrease in the small nerve fibre count is effective in treating neuropathic pain (NP). Sensory changes after capsaicin application, their correlation with pain relief and their role as possible predictors of response have been insufficiently analysed. We hypothesized a positive correlation between pain relief and increase in the warmth detection threshold (WDT), indicating loss of C-fibre function, and higher response rates in patients with preserved C-fibre function or heat hyperalgesia before application. METHODS: Quantitative Sensory Testing (DFNS protocol) was conducted in 20 unilaterally treated patients with peripheral NP (peripheral nerve injury: n = 14, polyneuropathy: n = 4, postherpetic neuralgia: n = 2) before and 2, 4, 6 and 8 weeks after application of capsaicin (8%) in this open-label study. Response was defined as ≥30% or ≥2 (Numeric Rating Scale: 0-10) decrease of current pain at any follow-up compared to baseline. RESULTS: In all patients, WDT significantly increased 8 weeks after capsaicin application, but did not correlate with pain relief in responders (n = 10, r = 0.179, p = 0.141). Before treatment, responders showed significantly higher z-values for the cold (CPT, +0.7 ± 1.1 vs. -0.4 ± 0.9) and mechanical pain threshold (MPT; 0.7 ± 2.5 vs. -1.2 ± 1.3), but did not differ from non-responders regarding WDT or heat pain threshold. A sum of the z-values for CPT and MPT >0.8 before treatment identified responders with 100% specificity and 70% sensitivity. CONCLUSIONS: Efficacy of capsaicin does not correlate with the induced loss of function of small fibres, measured by QST. Presence of cold and pinprick hyperalgesia seems to be predictive of response to capsaicin (8%).

Developmental and sex differences in somatosensory perception--a systematic comparison of 7- versus 14-year-olds using quantitative sensory testing.

There are controversial discussions regarding developmental- and sex-related differences in somatosensory perception, which were found, eg, when comparing younger children (6-8 years), older children (9-12 years), and adolescents (13-16 years) using quantitative sensory testing (QST). The aim of our current study was to systematically assess the impact of age and sex using the QST protocol of the German Research Network on Neuropathic Pain (DFNS). QST, including thermal and mechanical detection and pain thresholds, was assessed in 86 healthy 7-year-old children (42 girls and 44 boys) and 87 healthy 14-year-old adolescents (43 girls and 44 boys). The sample size was calculated a priori to detect medium-sized effects as found in the previous studies with adequate power. Developmental and sex differences were tested using univariate analysis of variance. Children were more sensitive to most pain stimuli, except cold pain stimuli, compared with adolescents, but did not differ in mechanical and thermal detection thresholds except in regard to cold stimuli. Sex had an impact only on warm detection, with girls being more sensitive. There were no interactions between age and sex. In conclusion, developmental changes during the puberty appear to influence pain perception, whereas sex effects in childhood are negligible. At present, it is not clear what brings about the differences between adult men and women that are apparent in epidemiological studies. Our results contradict the hypothesis that differences in peripheral nerve-fiber functioning underlie sex effects.

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes.

Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind-up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism-based classification feasible.